Project Summary Insufficient or excessive immune responses to pathogen infection are major causes of disease. Increasing evidence indicates that the nervous system regulates the immune system to help maintain immunological homeostasis. However, the precise mechanisms of this regulation are largely unknown. While many aspects of neural regulation of immunity are difficult to dissect in complex mammalian systems, the nematode Caenorhabditis elegans is an excellent model organism for such studies due to its simple, well-defined nervous system and an immune system that resembles the human innate immune system in several key respects. By using C. elegans, we demonstrated that neurotransmitter octopamine released from two interneurons designated as RIC binds to a G protein-coupled receptor OCTR-1, which, in turn, functions in the sensory ASH neurons to suppress innate immune response in non-neural tissues. We propose to dissect the neuronal and molecular mechanisms of this octopaminergic immuno-inhibitory pathway. We will determine where the immuno-modulatory signals originate in the OCTR-1 neural circuit, how the signals are relayed from the circuit to the non-neural tissues, what molecules in the non-neural tissues mediate innate immune responses, and how octopamine level is regulated in C. elegans in response to pathogen infection.The successful completion of this work will provide significant new data necessary to understand the neuronal and molecular mechanisms underlying neural control of innate immunity in mammals. As excessive innate immune responses have been linked to human health conditions such as Crohn's disease, rheumatoid arthritis, atherosclerosis, diabetes and Alzheimer's disease, the octopaminergic immuno-inhibitory pathway can be exploited to therapeutic advantage.